Cancer treatment

ABSTRACT

The invention relates generally to the treatment of cancer. One embodiment of the invention provides a method of treating cancer in an individual, the method comprising: administering to the individual an effective amount of trichostatin A (TSA).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending U.S. patentapplication Ser. No. 15/980,644, filed 15 May 2018, which is acontinuation application of then co-pending U.S. patent application Ser.No. 14/912,077, filed 12 Feb. 2016, which is the US National Phase ofPCT/US14/52209, filed 22 Aug. 2014, which claims priority to U.S.Provisional Patent Application Ser. No. 61/869,039, filed 22 Aug. 2013,each of which is hereby incorporated herein.

BACKGROUND

Histone deacetylase (HDAC) inhibitors have been investigated for theiruse in cancer therapies due to their ability to inhibit tumor cellgrowth with comparatively little toxicity. Known HDAC inhibitorsinclude, for example, rocilinostat (ACY-1215), Zolinza (vorinostat),abexinostat hydrochloride (PCI-24781), suberoylanilide hydroxamic acid(SAHA), valporic acid (VPA), Pracinostat (SB939), PCI-24781(CRA-024781), JNJ-26481585, Mocetinostat (MGCD0103, MG0103),Droxinostat, MC1568, Givinostat (ITF2357), Tubastatin A HCl, PCI-34051,Tacedinaline (CI994), and Panobiostat (LBH589, NVP-LBH589).

Aurora Kinase A (AURKA) is one member of a serine and threonine kinasefamily known to be important in maintaining normal mitotic chromosomalsegregation. Its protein localizes in the centrosomes of interphasecells and in the spindle of mitotic cells. AURKA overexpression has beenlinked with carcinogenesis in humans and has been detected in tumors ofthe breast, gastric tissues, colorectal tissue, bladder, pancreas,ovaries, prostate, and lung. It is possible, however, for any cancer tooverexpress AURKA, which may be determined, for example, by testing atumor for AURKA overexpression. Inhibition of AURKA expression has beenshown to reduce cell invasion in vivo. As such, AURKA, too, is a cancertreatment target, typically through small molecule inhibition. KnownAURKA inhibitors include, for example, VE465, tozasertib (VX-680),MK-0457, MK-5108, Alisertib (MLN8237).

Due to the efficacy of HDAC inhibitors and AURKA inhibitors in blockingcancer progression on their own, studies have evaluated the effect oftheir combined administration in non-human cancer models. For example,Li et al. found that co-treatment with VPA and VE465 induced moreapoptosis than either compound did alone. Similarly, Okabe et al. founda synergistic inhibitory effect on the proliferation of cancer cellsthrough the administration of either vorinostat or pracinostat incombination with tozasertib. The studies leading to the discovery of thepresent invention were undertaken since even though the dual HDAC andAURKA blocking effect was desirable in the treatment of cancer, nosingle entity is generally known to have this dual effect.

SUMMARY

One embodiment of the invention provides a method of treating cancer inan individual, the method comprising: administering to the individual aneffective amount of trichostatin A (TSA).

Another embodiment of the invention provides a pharmaceuticalcomposition comprising: trichostatin A (TSA) as a sole or primary aurorakinase A (AURKA) inhibitor; and a pharmaceutically-acceptable excipientor carrier.

In another embodiment, the invention provides a method of treating acancer in an individual, the method comprising: determining, from atumor sample obtained from the individual's body, a level of aurorakinase A (AURKA) expression; and in the case that the level of AURKAexpression is indicative of overexpression, administering to theindividual an effective amount of trichostatin A (TSA).

In still other embodiments of the invention, treatment with TSA iscombined with one or more other cancer treatments. Such other treatmentsmay include, for example, small molecule AURKA inhibition. Such acombined treatment may, in some cases, decrease the AURKA level to nearzero.

DETAILED DESCRIPTION

Trichostatin A (TSA or7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide),is an antifungal antibiotic and a known class I and II HDAC inhibitor.The structure of TSA is shown in Formula I below.

Applicants have surprisingly found that TSA, although previously knownas an HDAC inhibitor, is also capable of inhibiting AURKA expression. Assuch, TSA may be used as the primary or sole AURKA inhibitor in thetreatment of cancers. Cancers that may be treated according toembodiments of the invention include, for example, breast cancer,gastric cancer, colon cancer, rectal cancer, bladder cancer, pancreaticcancer, ovarian cancer, prostate cancer, lung cancer, hematologicalcancer, skin cancer, and malignancies.

A human retinal pigment epithelial cell line was treated withtrichostatin or vehicle for 24 hours and gene expression for 22,238probe sets covering 12,490 genes was generated using an Affymetrixinstrument. The effect of trichostatin A on AURKA expression is shownbelow in Table 1, and indicates a clear more than ten-folddownregulation of AURKA expression.

TABLE 1 Fold expression InstanceID Probe Rank change GeneName Gene10005532 208079_s_at 22253 −20.0837023  aurora AURKA kinase A 10005533208079_s_at 22245 −18.95510102 aurora AURKA kinase A 10005533204092_s_at 22238 −17.32256882 aurora AURKA kinase A 10005532204092_s_at 22227 −15.79825298 aurora AURKA kinase A 10005542204092_s_at 22222 −14.33801143 aurora AURKA kinase A 10005542208079_s_at 22221 −14.19814583 aurora AURKA kinase A

These results support the use of TSA in the treatment of cancer. Forexample, an individual may be treated for cancer by administering to theindividual an effective amount of TSA, wherein the effective amount isan amount sufficient to inhibit expression of AURKA in the individual.Such an amount may also be sufficient to inhibit HDAC activity in theindividual. In some embodiments of the invention, the effective amountis between about 0.1 mg/kg/day and about 10 mg/kg/day, e.g., betweenabout 0.5 mg/kg/day and about 5 mg/kg/day.

In some embodiments, treating the individual may further comprisedetermining, from a tumor sample obtained from the individual's body, alevel of AURKA expression. Such determining may include any known orlater-developed method or technique, including, for example,quantitative antigen-antibody interactions, the use of labelednucleotide probes, etc.

TSA may be administered to the individual to be treated in the form of apharmaceutical composition. Pharmaceutical compositions to be usedaccording to various embodiments of the invention comprise atherapeutically effective amount of TSA or an active metabolite of TSA,or a pharmaceutically acceptable salt or other form (e.g., a solvate)thereof, together with one or more pharmaceutically acceptableexcipients or carriers. The phrase “pharmaceutical composition” refersto a composition suitable for administration in medical use. It shouldbe appreciated that the determinations of proper dosage forms, dosageamounts, and routes of administration for a particular patient arewithin the level of ordinary skill in the pharmaceutical and medicalarts.

Administration may be oral but other routes of administration may alsobe employed, e.g., parenteral, nasal, buccal, transdermal, sublingual,intramuscular, intravenous, rectal, vaginal, etc. Solid dosage forms fororal administration include capsules, tablets, pills, powders, andgranules. In such solid dosage forms, the compound is admixed with atleast one inert pharmaceutically-acceptable excipient such as (a)fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate, (e) solution retarders, as for example paraffin, (f)absorption accelerators, as for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol, and glycerolmonostearate, (h) adsorbents, as for example, kaolin and bentonite, and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents. Solid dosage forms such as tablets,dragees, capsules, pills, and granules also can be prepared withcoatings and shells, such as enteric coatings and others well known inthe art. The solid dosage form also may contain opacifying agents, andcan also be of such composition that they release the active compound orcompounds in a certain part of the intestinal tract in a delayed manner.Examples of embedding compositions which can be used are polymericsubstances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients. Such solid dosage forms may generallycontain from 1% to 95% (w/w) of the active compound. In certainembodiments, the active compound ranges from 5% to 70% (w/w).

Solid compositions for oral administration can be formulated in a unitdosage form, each dosage containing from about 1 mg to about 500 mg ofactive ingredient. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activeingredient calculated to produce the desired effect over the course of atreatment period, in association with the required pharmaceuticalcarrier. TSA can be formulated, e.g., in a unit dosage form that is acapsule having 1-500 mg of active in addition to excipients.

Liquid dosage forms for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrups,and elixirs. In addition to the compound or composition, the liquiddosage forms may contain inert diluents commonly used in the art, suchas water or other solvents, solubilizing agents and emulsifiers, as forexample, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propyleneglycol,1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseedoil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil,glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acidesters of sorbitan or mixtures of these substances. Besides such inertdiluents, the composition can also include adjuvants, such as wettingagents, emulsifying and suspending agents, sweetening, flavoring, andperfuming agents.

In some embodiments of the invention, TSA is provided in a liquid formand administered to an individual intravenously.

While this invention has been described in conjunction with the specificembodiments outlined above, it is evident that many alternatives,modifications and variations will be apparent to those skilled in theart or are otherwise intended to be embraced. Accordingly, theembodiments of the invention as set forth above are intended to beillustrative, not limiting. Various changes may be made withoutdeparting from the spirit and scope of the invention as defined in thefollowing claims. All patents, patent application, scientific articlesand other published documents cited herein are hereby incorporated intheir entirety for the substance of their disclosures.

What is claimed is:
 1. In a method of treating a patient diagnosed withcancer with trichostatin A (TSA), the improvement comprising: selectingfor treatment a patient determined to have increased aurora kinase A(AURKA) expression, wherein the treating includes administering TSA tothe selected patient in an amount sufficient to decrease an AURKA levelin the selected patient, and wherein TSA is the only AURKA inhibitoradministered to the individual.
 2. The improvement of claim 1, whereinthe amount of TSA is sufficient to inhibit histone deacetylase (HDAC)activity in the selected patient.
 3. The improvement of claim 1, whereinthe amount of TSA is between about 0.1 mg/kg/day and about 10 mg/kg/day.4. The improvement of claim 3, wherein the amount of TSA is betweenabout 0.5 mg/kg/day and about 5 mg/kg/day.
 5. The improvement of claim1, wherein the cancer includes at least one cancer selected from a groupconsisting of: breast cancer, gastric cancer, colon cancer, rectalcancer, bladder cancer, pancreatic cancer, ovarian cancer, prostatecancer, lung cancer, hematological cancer, skin cancer, andmalignancies.
 6. The improvement of claim 1, wherein the TSA isadministered orally.
 7. The improvement of claim 1, wherein the TSA isadministered intravenously.
 8. The improvement of claim 1, furthercomprising: determining, from a tumor sample obtained from the selectedpatient's body, a level of aurora kinase A (AURKA) expression.
 9. Theimprovement of claim 1, wherein the cancer is breast cancer.